The present invention relates to 4-quinolinylmethanol derivatives and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to adenosine receptors and particularly adenosine A2A receptors, and to the treatment of movement disorders such as Parkinson""s disease.
Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson""s disease, Alzheimer""s disease, Huntington""s chorea and Wilson""s disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
There are four classic symptoms of Parkinson""s disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson""s disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson""s disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson""s disease are manifested.
Current strategies for the treatment of Parkinson""s disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl(copyright)), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when xe2x80x9con-offxe2x80x9d symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson""s disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.
Blockade of A2 adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson""s disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65). The potential utility of adenosine A2A receptor antagonists in the treatment of movement disorders such as Parkinson""s Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).
Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5,547-558).
Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A1, A2A, A2B (of high and low affinity) and A3 (Fredholn, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).
The design of P1 receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson""s disease (Williams, M. and Bumnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)
The pharmacology of adenosine A2A receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A2 adenosine receptors is the evidence of a functional link between adenosine A2A receptors to dopamine D2 receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482-487).
As a result of these investigations into the functional role of adenosine A2A receptors in the CNS, especially in vivo studies linking A2 receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 1624; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A2A receptors as potentially effective treatments for Parkinson""s disease.
While many of the potential drugs for treatment of Parkinson""s disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A2A antagonist therapy is that the underlying neurodegenerative disorder is also treated. The neuroprotective effect of adenosine A2A antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 30-48).
Xanthine derivatives have been disclosed as adenosine A2 receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A2 receptors, such as Parkinson""s disease (see, for example, EP-A-565377).
One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).
Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A1 and A2A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson""s disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994,46, 515-517).
KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] is a selective adenosine A2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352). Recent data has also been provided on the A2A receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507-513).
New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A2A Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).
The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A2A receptors.
It has now been found that 4-quinolinemethanol derivatives, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P1) receptors, and in particular at the adenosine A2A receptor. Such compounds may therefore be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. These may include Parkinson""s disease, Alzheimer""s disease, spasticity, Huntingdon""s chorea and Wilson""s disease.
According to the present invention there is provided use of a compound of formula (I): 
wherein:
R1 is hydrogen or alkyl;
R2 and R3 are independently selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered unbridged saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6 or 7 membered saturated or partially unsaturated carbocyclic ring or a 3, 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N;
or R1 and R2 or R3 together may form a 3, 4, 5, 6, 7 or 8 membered oxygen-containing saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
or R1 and R2 and R3 together may form a 4, 5, 6, 7 or 8 membered oxygen-containing partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N in which R2 and R3 together form a double bond;
wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated may be fused to an aryl ring; and
R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, alkyl, aryl, 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy, aryloxy, COR10, OCOR10, CO2R10, SR10, SOR10, SO2R10, SO2NR10R11, CONR10R11, CONR10NR11R12, OCONR10R11, NR10R11, NR10COR11, NR10CONR11R12, NR10CO2R11, NR10SO2R11, CR10NOR11, NR10CONR11NR12R13, NR10 NR11CO2R12, NR10NR11CONR12R13, NR10NR11COR12, NR10NR11SO2R12, SO2NR10NR11R12, NR10SO2NR11NR12R13 and NR10SO2NR11R12 wherein R10, R11, R12 and R13 are independently selected from hydrogen, alkyl and aryl,
or a pharmaceutically acceptable salt or prodrug thereof, with the proviso that where R1 and R4 to R9 are hydrogen, R2 or R3 is not 3-methoxy-4-benzyloxyphenyl or 2-dimethylaminoethoxymethyl, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A2A receptors, may be beneficial.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5, C6 or C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
As used herein, the term xe2x80x9carylxe2x80x9d means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more heteroatom, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pryazolyl, triazolyl, imidazolyl or pyrimidinyl.
The alkyl and aryl groups may be substituted or unsubstituted. Where any of R2 to R9 are selected from 4, 5, 6, 7 or 8 membered saturated or partially-unsaturated heterocyclic rings, the ring may be substituted or unsubstituted. Where R2 and R3 together form a carbocyclic or heterocyclic ring, the ring may be substituted or unsubstituted. Where R1 and R2 and/or R3 together form an oxygen-containing heterocyclic ring, the ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include: carbon-containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted
and unsubstituted benzyl); halogen atoms and halogen-containing groups such as
haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),
ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl),
acids (e.g. carboxy, carboxyalkyl),
acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl),
amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl),
carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylamninocarbonyloxy, arylaminocarbonyloxy)
and ureas (e.g. mono- or di-alkylaminocarbonylamino or arylaminocarbonylamino);
nitrogen-containing groups such as
amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur-containing groups such as
thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuiranyl, isobenzofimranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94 and xe2x80x9calkoylxe2x80x9d means alkyl-COxe2x80x94. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
As used herein the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of the compound of formula (I).
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids, and most particularly preferred is the hydrochloric salt. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
As used herein, the term xe2x80x9csaturated heterocyclic ringxe2x80x9d means a heterocyclic ring wherein the bonds between the atoms forming the ring are single bonds. Examples of such saturated heterocyclic rings include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, heptamethyleneiminyl, oxiranyl, oxetanyl tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyran, piperazinyl, morpholinyl, dioxanyl and thiomorpholinyl
As used herein, the term xe2x80x9cpartially unsaturated heterocyclic ringxe2x80x9d means a heterocyclic ring wherein one or more of the bonds between the atoms forming the ring are unsaturated bonds and wherein the ring is non-aromatic in character. Examples of such partially unsaturated rings include 3-pyrrolinyl, imidazolinyl, oxazolinyl, thiazolinyl, pyrrazolinyl, dihydropyranyl, pyranyl, dihydropyridinyl and tetrahydropyridinyl.
As used herein, the term xe2x80x9ccarbocyclic ringxe2x80x9d means a ring wherein the atoms forming the ring are carbon atoms and wherein the ring is either (a) a saturated ring in which the bonds between the ring atoms are single bonds (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; or a bicyclic ring such as norbornanyl); or (b) a partially unsaturated ring wherein one or more of the bonds between the ring atoms are unsaturated bonds and wherein the ring is non-aromatic in character (such as cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cycloheptadienyl); or (c) an aromatic ring (such as phenyl).
As used herein, the term xe2x80x9cunbridgedxe2x80x9d refers to a ring or ring system which is not bridged; the term xe2x80x9cbridgedxe2x80x9d referring to a ring system in which two or more rings share non-adjacent atoms to form a multicyclic ring system. Examples of a bridged ring system include adamantane, norbornane and 5-ethenyl-1-azabicyclo[2.2.2]octane.
As used herein, the term xe2x80x9cfusedxe2x80x9d refers to a ring system in which two rings or ring systems share only adjacent ring atoms. Examples of a fused ring system include naphthalene, quinoline, indan and benzofuran.
Where any of R2 to R9 are selected from 4, 5, 6, 7 or 8 membered heterocyclic rings containing a plurality of heteroatoms selected from O, S and N, the heteroatoms may be the same or different.
Where R2 and R3 together form a 3, 4, 5, 6, 7 or 8 membered heterocyclic ring containing a plurality of heteroatoms selected from O, S and N, the heteroatoms may be the same or different.
Where R1 and R2 and/or R3 form an oxygen-containing ring containing one or more additional heteroatoms selected from O, S and N, the heteroatoms in said ring may be the same or different.
Where R1 and R2; or R1 and R3; or R2 and R3 together form a 3 membered heterocyclic ring, it is preferred that said ring is saturated and contains no more than one heteroatom.
In an embodiment of the invention, R1 is hydrogen or alkyl and R2 and R3 are independently selected from hydrogen, alkyl (including cycloalkyl, ara-alkyl and heteroara-alkyl), aryl (including heteroaryl) and 4, 5, 6, 7 or 8 membered unbridged saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring when partially unsaturated may be fused to an aryl ring.
In an alternative embodiment of the invention, R1 is hydrogen or alkyl and R2 and R3 together form a 3, 4, 5, 6 or 7 membered saturated or partially unsaturated carbocyclic ring or a 3, 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N, wherein said carbocyclic or heterocyclic ring when partially unsaturated may be fused to an aryl ring.
In a further alternative embodiment of the invention, R1 and either R2 or R3 together form a 3, 4, 5, 6, 7 or 8-membered oxygen-containing saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, wherein said heterocyclic ring when partially unsaturated may be fused to an aryl ring. In this embodiment, the R2 or R3 group which has not formed said heterocyclic ring with R1 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8-membered unbridged saturated or partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring when partially unsaturated may be fused to an aryl ring.
In a further alternative embodiment of the invention, R1 and R2 and R3 together form a 4, 5, 6, 7 or 8 membered oxygen-containing partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N in which R2 and R3 together form a double bond, wherein said heterocyclic ring may be fused to an aryl ring. In this embodiment, preferably said oxygen-containing heterocyclic ring is aromatic.
In the compounds of formula (I), where R2 and R3 are independently selected from unbridged saturated and partially unsaturated heterocyclic rings, said heterocyclic ring is preferably a heterocyclic ring in which the one or more heteroatoms are selected only from O and S; is preferably monocyclic; and is preferably a 5 or 6-membered ring. Where said heterocyclic ring is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably a phenyl ring.
In the compounds of formula (I), where R2 and R3 together form a carbocyclic ring, said carbocyclic ring is preferably unbridged; preferably monocyclic; and is preferably a 5 or 6-membered ring. Where said carbocyclic ring is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably a phenyl ring.
In the compounds of formula (I), where R2 and R3 together form a heterocyclic ring, said heterocyclic ring is preferably a heterocyclic ring in which the one or more heteroatoms are selected only from O and S; is preferably unbridged; is preferably monocyclic; and is preferably a 4, 5 or 6-membered ring. Where said heterocyclic ring is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably a phenyl ring.
In the compounds of formula (I) where R1 and R2 or R3 together form a heterocyclic ring, said heterocyclic ring is preferably a heterocyclic ring in which the one or more heteroatoms are selected only from O and S; is preferably unbridged; and is preferably monocyclic. It is preferred that this heterocyclic ring contains 3, 4, 5 or 6 ring atoms, preferably 3, 5 or 6 ring atoms. Where the heterocyclic ring is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably a phenyl ring.
In the compounds of formula (a) where R1 and R2 and R3 together form a heterocyclic ring, said heterocyclic ring is preferably a heterocyclic ring in which the one or more heteroatoms are selected only from O and S; is preferably unbridged; and is preferably monocyclic. It is preferred that this heterocyclic ring contains 4, 5 or 6 ring atoms, preferably 5 or 6 ring atoms. Where the heterocyclic ring is fused to an aryl ring, said aryl ring is preferably a phenyl ring.
Preferably, the compounds of formula (I) are selected from compounds in which R1 is hydrogen or methyl.
Preferably, the compounds of formula (I) are selected from compounds in which R2 is hydrogen or methyl or compounds in which R2 together with R3 forms a ring, as defined above.
In the compounds of formula (I), where R2 and/or R3 is selected from alkyl, then preferably R2 and/or R3 is selected from methyl, isopropyl, cyclohexyl and benzyl. In one embodiment, at least one of R2 and R3 is selected from alkyl, aryl and heterocyclic rings as defined above, and preferably from alkyl.
In the compounds of formula (I), where R2 and/or R3 is selected from aryl, then preferably R2 and/or R3 is selected from 5 or 6-membered aromatic rings. In an embodiment of the invention, R2 and/or R3 is selected from carbocyclic aromatic rings and heteroaromatic rings containing heteroatoms other than nitrogen. In a further embodiment, R2 and/or R3 is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl and 2-pyridyl, more preferably from phenyl, 2-thienyl, 3-thienyl, 2-furyl and 3-furyl, and more preferably from 2-thienyl, 3-thienyl, 2-furyl and 3-furyl.
In the compounds of formula (I), it is preferred that where one or both of R2 and R3 is selected from aryl, then said aryl is other than 3-methoxy-4-benzyloxyphenyl, preferably other than alkoxy-substituted phenyl, preferably other than alkoxy-substituted aryl. Where one or both of R2 and R3 is selected from alkyl, it is preferred that said alkyl group is other than 2-dimethylaminoethoxymethyl, preferably other than an ethoxymethyl group, preferably other than an alkoxymethyl group, and preferably other than an alkoxyalkyl group, particularly wherein said ethoxymethyl or said alkoxymethyl or said alkoxyalkyl group is substituted and more particularly wherein said ethoxymethyl or said alkoxymethyl or said alkoxyalkyl is substituted by a nitrogen-containing group (such as amino, amino or a nitrogen-containing heterocyclic group).
R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl), ara-alkyl and heteroara-alkyl), aryl (including heteroaryl), 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy (including fluorinated alkoxy), aryloxy, COR10, OCOR10, CO2R10, SR10, SOR10, SO2R10, SO2NR10R11, CONR10R11, CONR10NR11R12, OCONR10OR11, NR10R11, NR10COR11, NR10CONR11R12, NR10CO2R11, NR10SO2R11, CR10NOR11, NR10CONR11NR12R13, NR10NR11CO2R12, NR10NR11CONR12R13, NR10NR11COR12, NR10NR11SO2R12, SO2NR10NR11R12, NR10SO2NR11NR12R13 and NR10SO2NR11R12 wherein R10, R11, R12 and R13 are independently selected from hydrogen, alkyl and aryl.
In one embodiment of the invention, R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen; alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl), ara-alkyl and heteroara-alkyl); aryl (including heteroaryl); 4, 5, 6, 7 or 8 membered saturated heterocyclic rings containing one or more heteroatoms selected from O, S and N; hydroxy; halogen; nitro; cyano; alkoxy (including fluorinated alkoxy); aryloxy; COR10; OCOR10; CO2R10; SR10; SOR10; SO2R10; SO2NR10R11; CONR10R11; CONR10NR11R12; OCONR10R11; NR10COR11; NR10CONR11; NR10CONR11R12, NR10CO12R11; NR10SO2R11; CR10NOR11; NR10CONR11NR12R13; NR10NR11CO2R12; NR10NR11CONR12R13; SO2NR10NR11R12; NR10SO2NR11NR12R13; and NR10SO2NR11R12, wherein R10, R11, R12 and R13 are independently selected from hydrogen, alkyl and aryl.
In an embodiment of the invention, where any of R4 to R9 are selected from heterocyclic rings, said ring is unbridged and preferably monocyclic. In a further embodiment of the invention, where any of R4 to R9 are independently selected from NR10COR11 then R10 of the or each NR10COR11, group is hydrogen.
It is preferred that at least one of R4 to R9 is a group other than hydrogen.
In an embodiment of the invention, the compounds of formula (I) are selected from compounds other than compounds in which both R4 and R9 are halo-alkyl (including trifluoromethyl). In an embodiment of the invention, R4 and/or R9 are independently selected from hydrogen, alkyl (preferably unsubstituted alkyl and preferably methyl or ethyl), aryl (preferably phenyl), alkoxy (preferably methoxy), hydroxy, halogen, NR10R11(preferably where R10 and R11 are independently selected from hydrogen and alkyl (including cycloalkyl and ara-alkyl), preferably methyl, cyclohexyl or benzyl), COR10 (preferably where R10 is selected from hydrogen and alkyl (preferably methyl)), CO2R10 (preferably where R10 is hydrogen or alkyl, preferably methyl), SR10 (Preferably where R10 is alkyl, preferably methyl), SO2R10 (preferably where R10 is alkyl, preferably methyl) and CONR10R11 (preferably where R10 and R11 are independently selected from hydrogen and alkyl (including ara-alkyl), preferably methyl).
Preferably, the compounds of formula (I) are selected from compounds in which R5 is hydrogen or alkyl, preferably hydrogen or methyl. Preferably, the compounds of formula (I) are selected from compounds in which R6, R7 and/or R9 is hydrogen.
In an embodiment of the invention, the compounds of formula (I) are selected from:
2,8-bis(trifluoromethyl)-xcex1-(3-thienyl)-4-quinolinemethanol;
2,8-bis(trifluoromethyl)-xcex1-cyclohexyl-4-quinolinemethanol;
2,8-bis(trifluoromethyl)-xcex1-(2,6-dichlorophenyl)-4-quinolinemethanol;
2,8-bis(trifluoromethyl)-xcex1-(2-bromophenyl)-4-quinolinemethanol;
2,8-bis(trifluoromethyl)-xcex1-(2-methoxyphenyl)-4-quinolinemethanol;
8-methyl-xcex1-(3-thienyl)-2-trifluoromethyl-4-quinolinemethanol;
xcex1-cyclohexyl-8-methyl-2-trifluoromethyl-4-quinolinemethanol, and
xcex1-cyclohexyl-2-hydroxy-4-quinolinemethanol.
Where chiral, the compounds of formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.
According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
The disorder may be caused by the hyperfunctioning of the purine receptors.
According to a further aspect of the present invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.
According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
According to a further aspect of the invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.
According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.
According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
(i) compounds in which R2 and R3 are selected from methyl, phenyl and substituted phenyl, R4 is phenyl or substituted phenyl and R1 and R5 to R9 are hydrogen;
(ii) compounds in which R2 or R3 is methyl or isopropyl and R4 and R9 are CF3;
(iii) compounds in which R2 or R3 is acyclic C1 to C5 alkyl substituted by phenyl or by an N-containing heterocycle or by a mono- or di-alkyl amino group or by a (dialkylamino)alkoxy group;
(iv) compounds in which R2 or R3 is pyridyl, indole, pyrimidine, piperidine, piperazine or pyrrolidine;
(v) compounds in which R4 is thienyl and R1 to R3 and R5 to R9 are hydrogen;
(vi) compounds in which R1 and either R2 or R3 together form a 3-membered oxygen-containing saturated heterocyclic ring; and
(vii) compounds in which R1 and R2 and R3 together form a 5-membered oxygen-containing partially-unsaturated or aromatic heterocyclic ring.
In an alternative embodiment, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
(i) compounds in which R2 and R3 are selected from methyl, phenyl and substituted phenyl;
(ii) compounds in which R2 or R3 is acyclic saturated alkyl and R4 and R9 are CF3;
iii) compounds in which R2 or R3 is alkyl substituted by phenyl or by an N-containing heterocycle or by a mono- or di-alkyl amino group or by a (dialkylamino)alkoxy group;
iv) compounds in which R2 or R3 is a heterocyclic ring in which the ring atoms are selected only from carbon and nitrogen;
v) compounds in which R4 is thienyl;
vi) compounds in which R1 and either R2 or R3 together form an oxygen-containing saturated heterocyclic ring; and
vii) compounds in which R1 and R2 and R3 together form an oxygen-containing partially unsaturated or aromatic heterocyclic ring.
In a further alternative embodiment, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
(i) compounds in which R2 and R3 are selected from carbocyclic aromatic groups;
(ii) compounds in which R2 and/or R3 are selected from acyclic saturated alkyl;
(iii) compounds in which R2 or R3 is alkyl substituted by aryl or by a saturated N-containing heterocycle or by a mono- or di-alkyl amino group or by a (dialkylamino)alkoxy group;
(iv) compounds in which R2 or R3 is an N-containing heterocyclic ring;
(v) compounds in which R4 is an S-containing heterocyclic ring; and
(vi) compounds in which R1 and R2 and/or R3 together form an oxygen-containing heterocyclic ring.
According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein:
(i) R3 is a 5 or 6 membered unbridged saturated, partially-unsaturated or aromatic heterocyclic ring in which the one or more heteroatoms are selected only from O and S; or
(ii) R3 is a 3, 4, 5, 6 or 7 membered carbocyclic ring; or
(iii) R2 and R3 together form a 3, 4, 5 or 7 membered saturated or partially-unsaturated carbocyclic ring, or a 4, 5, 6 or 7 membered saturated or partially-unsaturated heterocyclic ring in which the one or more heteroatoms are selected only from O and S, or a 4, 5 or 7 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from N, and preferably a 3, 4, 5 or 7 membered saturated or partially-unsaturated carbocyclic ring or a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring in which the one or more heteroatoms are selected only from O and S; or
(iv) R1 is C1 to C4 acyclic alkyl and R3 is aryl (including heteroaryl) or C3 to C7 cycloalkyl; or
(v) R1 is C1 to C4 acyclic alkyl and R2 and R3 together form a 3, 4, 5, 6 or 7 membered saturated or partially-unsaturated carbocyclic ring or a 3, 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N;
wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated or aromatic is optionally fused to an aryl ring.
According to a further aspect of the invention there is provided for use in therapy a compound of formula (I) wherein R2 is H or alkyl, or a pharmaceutically acceptable salt or prodrug thereof.
The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
The disorders of particular interest are Parkinson""s disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson""s disease (punch-drunk syndrome).
Other movement disorders in which the therapy may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, Alzheimer""s disease or other disorders of the basal ganglia which result in abnormal movement or posture.
A further example of a disorder in which the blocking of purine receptors may be beneficial is depression.
The compound of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
The present invention may also be effective in treating Parkinson""s with on-off phenomena; Parkinson""s with freezing (end of dose deterioration); and Parkinson""s with prominent dyskinesias.
According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
(i) compounds in which R2 or R3 is selected from phenyl or substituted phenyl and R1 and R5 to R9 are selected from hydrogen;
(ii) compounds in which R2 or R3 is selected from phenyl or substituted phenyl and one or two of R5 to R9 is selected from Cl, Br, methoxy and NH2;
(iii) compounds in which R2 or R3 is methyl or isopropyl and R4 and R9 are CF3;
(iv) compounds in which R2 or R3 is methyl or ethyl and one or two of R5 to R9 is selected from NH2, Cl, F, methoxy, hydroxy and OC(O)NEt2;
(v) compounds in which R2 or R3 is methyl, ethyl, n-butyl, t-butyl, 2-phenylethenyl, 1-nitroethyl or 1-aminoethyl and R5 to R9 are selected from hydrogen;
(vi) compounds in which R2 or R3 is methyl or t-butyl and R7 and R9 are methyl;
(vii) compounds in which R2 or R3 is selected from CO2Et, C(NH)OEt and CF3 and four or five of R5 to R9 are selected from hydrogen;
(viii) compounds in which R2 or R3 is acyclic C1 to C5 alkyl substituted by phenyl or by an N-containing heterocycle or by a mono- or di-alkyl amino group or by a (dialkylamino)alkoxy group;
(ix) compounds in which R2 or R3 is pyridyl, indole, pyrimidine, piperidine, piperazine, pyrrolidine, 2-pyridyl-N-oxide;
(x) compounds in which R4 is thienyl and R1 to R3 and R5 to R9 are hydrogen;
(xi) compounds in which R2 and R3 together form a cyclohexyl group, a 2-cyclohexenyl group or an N-methyl-4-piperidyl group and R7 is selected from H, Cl, methyl or methoxy;
(xii) compounds in which R1 and either R2 or R3 together form an oxygen-containing saturated heterocyclic ring;
(xiii) compounds in which R1 and R2 and R3 together form a 5-membered oxygen-containing partially unsaturated or aromatic heterocyclic ring; and
(xiv) compounds in which R1 to R3 and R5 to R8 are hydrogen and R4 and R9 are CF3.
In an alternative embodiment of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
compounds in which R2 or R3 is selected from phenyl or substituted phenyl;
(ii) compounds in which R2 or R3 is acyclic saturated alkyl and R4 and R9 are CF3;
(iii) compounds in which R2 or R3 is selected from methyl, ethyl, n-butyl, t-butyl, 2-phenylethenyl, 1-nitroethyl, 1-aminoethyl, CO2Et, C(NH)OEt and CF3;
(iv) compounds in which R2 or R3 is alkyl substituted by phenyl or by an N-containing heterocycle or by a mono or di-alkyl amino group or by a (dialkylamino)alkoxy group;
(v) compounds in which R2 or R3 is a heterocyclic ring in which the ring atoms are selected only from carbon and nitrogen;
(vi) compounds in which R4 is thienyl;
(vii) compounds in which R2 and R3 together form a cyclohexyl group, a 2-cyclohexenyl group or an N-methyl-4-piperidyl group;
(viii) compounds in which R1 and R2 and/or R3 together form an oxygen-containing heterocyclic ring; and
(ix) compounds in which R1 to R3 are hydrogen and R4 and R9 are CF3.
In a further alternative embodiment of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:
(i) compounds in which R2 or R3 is selected from carbocyclic aromatic groups;
(ii) compounds in which R2 or R3 is selected from acyclic alkyl, CO2(alkyl) and C(NH)O(alkyl);
(iii) compounds in which R2 or R3 is alkyl substituted by aryl or by a saturated N-containing heterocycle or by a mono- or di-alkyl amino group or by a (dialkylamino)alkoxy group;
(iv) compounds in which R2 or R3 is an N-containing heterocyclic ring;
(v) compounds in which R4 is an S-containing heterocyclic ring;
(vi) compounds in which R2 and R3 together form a 6-membered carbocyclic group or a 6-membered N-containing heterocyclic ring;
(vii) compounds in which R1 and R2 and/or R3 together form an oxygen-containing heterocyclic ring; and
(viii) compounds in which R1 to R3 are hydrogen.
According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein:
(i) R3 is a 5 or 6 membered unbridged saturated, partially unsaturated or aromatic heterocyclic ring in which the one or more heteroatoms are selected only from O and S; or
(ii) R3 is a 3, 4, 5, 6 or 7 membered carbocyclic ring; or
(iii) R2 and R3 together form a 3, 4, 5 or 7 membered saturated or partially-unsaturated carbocyclic ring, or a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring in which the one or more heteroatoms are selected only from O and S, or a 4, 5 or 7 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from N, and preferably a 3, 4, 5 or 7 membered saturated or partially-unsaturated carbocyclic ring or a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring in which the one or more heteroatoms are selected only from O and S; or
(iv) R1 is C1 to C4 acyclic alkyl and R3 is aryl (including heteroaryl) or C3 to C7 cycloalkyl; or
(v) R1 is C1 to C4 acyclic alkyl and R2 and R3 together form a 3, 4, 5, 6 or 7 membered saturated or partially-unsaturated carbocyclic ring or a 3, 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N,
wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated or aromatic is optionally fused to an aryl ring.
According to a further aspect of the invention there is provided a compound of formula (I) wherein R2 is H or alkyl, or a pharmaceutically acceptable salt or prodrug thereof.
The invention further relates to the compounds disclosed herein.
According to a further aspect of the invention, there is provided a method of preparing the novel compounds of formula (I), and pharmaceutically acceptable salts and prodrugs thereof. Compounds of formula (I) may be prepared by conventional synthetic methods such as those illustrated in Reaction Scheme 1. 
Compounds of formula (1) where R1 is H and R2 to R9 are as defined above, are prepared by standard methods from 4-bromoquinolines (4) for example by initial reaction with a metallating reagent such as BuLi and reacting the subsequent metallated carbanion with a carbonyl-containing compound such as an aldehyde (R2CHO) or a ketone (R2COR3). Alternatively compounds of formula (1) where R1 is H are prepared from carbonyl-containing compounds (7) where R is R2 or alkoxy, either by reduction with a standard reducing agent such as NaBH4 or by addition of a carbanionic species such as an alkyl or aryl lithium reagent or a Grignard reagent. When compounds (7), where R is alkoxy are treated with a carbanionic species as above, the reaction conditions may be controlled by standard methods to preferentially give compounds (1) where R2=R3, or compounds (1) where R2 and R3 are different. Carbonyl-containing compounds (7) may be prepared from 4-bromoquinolines (4) by metallation as described above, followed by reaction with a carbonyl-containing compound such as an ester (RCO2alkyl) to give a ketone (7) where R is alkyl or aryl, a lactone to give a ketone (7) where R is hydroxyalkyl, an alkyl chlorofornate or dialkyl carbonate to give an ester (7) where R is alkoxy, or a dialkyl formamide (eg DMF) to give an aldehyde (7) where R is H.
Compounds of formula (1 ) where R1 is alkyl are prepared by standard methods from compounds of formula (1) where R1 is H for example by alkylation with an alkyl halide in the presence of a suitable base such as NaH.
Compounds of formula (1) where R1 is H and either R2 or R3 is substituted alkyl may also be prepared from epoxides (6) by reaction with an appropriate nucleophile. Treatment for example with an amine, alcohol or fluoride may lead to compounds of formula (1) where R1 is H and either R2 or R3 is an alkyl group substituted in the xcex2-position by an amine group, an ether group or a fluoro group. Epoxides (6) are either known in the literature or may be prepared from bromoketones (5) by standard literature methods such as, for example treatment with a reducing agent such as NaBH4. Bromoketones (5) are either known in the literature or are prepared from suitably substituted ketones (7) by standard methods such as xcex1-bromination.
Compounds of formula (1) where R1 together with its attached oxygen atom and together with R2 and R3 forms a partially unsaturated or aromatic 5-membered, oxygen-containing heterocyclic ring, such as for example a furan, may be prepared from 4-bromoquinolines (4) by standard methods such as a palladium-catalysed vinyl or aryl coupling reaction with an appropriately activated heteroaryl derivative such as an arylboronic acid. This methodology may be used to prepare compounds of formula (1) where R1 together with it""s attached oxygen atom and together with R2 and R3, form a variety of unsaturated 5-membered, oxygen-containing heterocyclic rings such as furans, benzofurans, oxazoles, benzoxazoles, isoxazoles, benzisoxazoles and oxadiazoles.
Compounds of formula (1) where R1 together with its oxygen atom and together with R2 or R3 forms a saturated or partially unsaturated 4, 5, 6, 7 or 8-membered oxygen-containing heterocyclic ring are prepared from compounds of formula (1) where R1 is H and R2 is an alkyl group substituted in an appropriate position with a suitable leaving group such as a tosylate, mesylate or halogen, by treatment with an appropriate base such as triethylamine.
Compounds of formula (1) where R2 is an alkyl group substituted with a leaving group may be prepared from compounds of formula (1) where R2 is an alkyl group substituted by a hydroxy group for example by treatment with p-toluenesulphonyl chloride or methanesulphonyl chloride in the presence of a suitable base such as triethylamine. In favourable cases conversion of the hydroxy group to a leaving group may result in spontaneous cyclisation to a compound of formula (1) where R1 together with it""s oxygen atom and together with R2 forms a saturated 4, 5, 6, 7, or 8-membered oxygen-containing heterocyclic ring.
Compounds of formula (1) where R1 is H and R2 is an alkyl group substituted in an appropriate position with a hydroxy group are prepared from ketones (7) where R is a hydroxyalkyl group by standard methods such as reduction with. for example, NaBH4.
Compounds of formula (1) where R4 an amino, alkylamino or arylamino (NR10R11), alkoxy, aryloxy, alkylthio or arylthio (SR10) or cyano group are prepared from compounds of formula (1) where R4 is a halogen, preferably bromine, by standard methods such as reaction with an appropriate nucleophilic reagent such as ammonia, an alkylamine, arylamine, alkoxide, aryloxide, alkylthiolate, arylthiolate or cyanide.
Compounds of formula (1) where R4 is an amino (NH2) group may also be prepared from compounds of formula (1) where R4 is a halogen in two steps by reaction with an amine which is substituted with a suitable protecting group such as a benzyl or substituted benzyl group, followed by a deprotection step where the amine protecting group is removed by standard methodology such as hydrogenation or treatment with strong acid.
Compounds of formula (1) where R4 is an alkylamino or dialkylamino group may also be prepared from compounds of formula (1), where R4 is an unsubstituted amino or mono-substituted amino group, by standard methods such as alkylation or dialkylation by reaction with, for example an alkyl halide in the presence of a suitable base, or alternatively by reductive alkylation by reaction with a suitable aldehyde or ketone in the presence of a suitable reducing agent such as NaCNBH3, or alternatively by acylation with a suitable acylating agent such as an acid chloride or anhydride, followed by reduction of the subsequent amide using a standard reagent such as BH3. Compounds of formula (1) where R4 is an amino, monoalkylamino or monoarylamino group (NHR10) may be converted by standard methods to compounds of formula (1) where R4 is NR10COR11, NR10CO2R11, NR10CONR11R12, or NR10SO2R11 for example by treatment with an acid chloride (R11COCl), chloroformate (ClCO2R11), isocyanate (R11NCO), chloroformamide (ClCONR11R12) or sulphonyl chloride (ClSO2R11) or by using one of a large variety of alternative reagents known to those skilled in the art.
Compounds of formula (1) where R4 is a substituted hydrazine group such as NR10NR11COR12, NR10NR11CO2R12, NR10NR11CONR12R13 or NR10NR11SO2R12 may be prepared from a compound of formula (1) where R4 is halogen by reaction with a suitably substituted hydrazine derivative or alternatively prepared from a compound of formula (1) where R4 is NR10NHR11, by reaction with, for example an acid chloride (R12COCl), chioroformate (ClCO2R12), isocyanate (R12NCO), chloroformamide (ClCONR12R13) or sulphonyl chloride (CISO2R12). Compounds of formula (1) where R4 is NR10NHR11 may be prepared from compounds of formula (1) where R4 is a halogen by treatment with hydrazine or a suitably substituted hydrazine derivative.
Compounds of formula (1) where R4 is a sulphoxide (SOR10) or sulphone (SO2R10) group are prepared from a compound of formula (1) where R4 is a thioether (SR10) by standard methods such as by treatment with a suitable oxidising agent such as m-chloroperbenzoic acid or alternative oxidising agent known to those skilled in the art to permit selective mono- or di-oxygenation.
Compounds of formula (1) where R4 is hydroxy (OH) are prepared from compounds of formula (1) where R4 is a halogen, preferably bromine, by standard methods such as hydrolysis with, for example aqueous acid.
Compounds of formula (1) where R4 is an alkoxy, acyloxy (OCOR10) or carbamate (OCONR10R11) group may be prepared from a compound of formula (1) where R4 is a hydroxy group by standard methods such as alkylation or acylation or by reaction with an appropriate isocyanate.
Compounds of formula (1) where R4 is an ester (CO2R10), aldehyde (CHO) or amide (CONR10R11) are prepared from compounds of formula (1) where R4 is a halogen, preferably bromine, by standard methods such as metallation with, for example BuLi to form a metallated carbanion, followed by reaction with, for example a chloroformate (ClCO2R10), dialkylformamide (for example DMF), isocyanate (R10NCO) or chloroformamide (ClCONR12R13).
Further modification of a compound of formula (1) where R4 is an ester, amide or aldehyde can lead, by using standard literature methods, to compounds of formula (1) where R4 is, for example a carboxylic acid, hydroxyalkyl, aminoalkyl, cyano, amidine, carboxylic hydrazide (CONR10NR11 R12) or oxime (CR10NOR11) group.
Further modification of a compound of formula (1) where R4 is an ester, amide, hydrazide, amidine, aldehyde, cyanide or carboxylic acid can lead, by using standard literature methods, to compounds of formula (1) where R4 is, for example a 5- or 6-membered heterocyclic ring such as an oxadiazole, thiadiazole, thiazole, oxazole, isoxazole, pyrazole, triazole, tetrazole, imidazole or pyrimidine.
4-Bromoquinolines (4) are either known in the literature or may be prepared from 4-hydroxyquinolines (3) by standard literature methods such as treatment with POBr3. 4-Bromoquinolines (4) where R4 is also a bromine atom are either known in the literature or are prepared directly from anilines (2) by treatment with, for example malonic acid or a suitably substituted malonic acid in the presence of POBr3. 4-Bromoquinolines (4) where R4 is also a bromine atom may also be prepared from known 4-hydroxyquinolines (3) where R4 is also hydroxy, by treatment with POBr3. 4-Hydroxyquinolines (3) are either known in the literature or may be prepared from anilines (2) by standard literature methods such as by reaction with a suitably substituted acetoacetate ester derivative in the presence of a suitable acid catalyst or dehydrating agent such as polyphosphoric acid. Anilines (2) are either commercially available, are known in the literature or may be prepared by standard literature methods.
Synthetic preparation of some of the compounds of formula (1) where R1-R9 are as defined above, may require the use of protecting groups to avoid certain functional groups interfering in the normal course of a reaction. The protecting groups used in the preparation of the compounds of formula (1) may be selected from a range of protecting groups commonly used in organic synthesis. This may include, for example the protection of amines with benzyl, substituted benzyl, diphenylmethyl or butoxycarbonyl groups or as a nitro group, the protection of alcohols with, for example benzyl, substituted benzyl, t-butyl or trialkylsilyl groups, and the protection of ketones as ketals or thioketals. In all cases deprotection of these functional groups is carried out by standard literature procedures known to those skilled in the art.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions employed in the present invention comprise a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and may also contain other therapeutic ingredients known to those skilled in the art.
Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I). For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration according to the present invention is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practical use, a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
Pharmaceutical compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of this invention.